Pexeva

CLINICAL PHARMACOLOGY

Pharmacodynamics

The efficacy of paroxetine in the treatment of MDD, OCD,
panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be
linked to potentiation of serotonergic activity in the central nervous system
resulting from inhibition of neuronal reuptake of serotonin
(5-hydroxytryptamine, 5-HT). Studies at clinically relevant doses in humans
have demonstrated that paroxetine blocks the uptake of serotonin into human
platelets. In vitro studies in animals also suggest that paroxetine is a potent
and highly selective inhibitor of neuronal serotonin reuptake and has only very
weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand
binding studies indicate that paroxetine has little affinity for muscarinic
alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and
histamine (H1)-receptors; antagonism of muscarinic, histaminergic, and
alpha1-adrenergic receptors has been associated with various anticholinergic,
sedative, and cardiovascular effects for other psychotropic drugs.

Because the relative potencies of paroxetine's major
metabolites are at most 1/50 of the parent compound, they are essentially
inactive.

Pharmacokinetics

Paroxetine mesylate is completely absorbed after oral
dosing of the mesylate salt. In a study in which normal male subjects (n=25)
received paroxetine 30 mg tablets daily for 24 days, steady-state paroxetine
concentrations were achieved by approximately 13 days for most subjects,
although it may take substantially longer in an occasional patient. At steady
state, mean values of Cmax, Tmax, Cmin, and T½ were 81.3 ng/ml (CV 41%), 8.1
hr. (CV 56%), 43.2 ng/ml (CV 52%), and 33.2 hr. (CV 52%), respectively. The
steady-state Cmax and Cmin values were about 7 and 10 times what would be
predicted from single dose studies. Steady-state drug exposure based on AUC0-24
was about 10 times greater than would have been predicted from single-dose data
in these subjects. The excess accumulation is a consequence of the fact that
one of the enzymes that metabolizes paroxetine is readily saturable.

In steady-state dose proportionality studies involving
elderly and nonelderly patients, at doses of 20 to 40 mg daily for the elderly
and 20 to 50 mg daily for the nonelderly, some nonlinearity was observed in
both populations, again reflecting a saturable metabolic pathway. In comparison
to Cmin values after 20 mg daily, values after 40 mg were only about 2 to 3
times greater than doubled.

The effects of food on the bioavailability of paroxetine
were studied in subjects administered a single dose with and without food. AUC
was only slightly increased (6%) when drug was administered with food but the Cmax
was 29% greater, while the time to reach peak plasma concentration decreased
from 6.4 hours post-dosing to 4.9 hours.

Paroxetine is extensively metabolized after oral
administration. The principal metabolites are polar and conjugated products of
oxidation and methylation, which are readily cleared. Conjugates with
glucuronic acid and sulfate predominate, and major metabolites have been
isolated and identified. Data indicate that the metabolites have no more than
1/50 the potency of the parent compound at inhibiting serotonin uptake. The
metabolism of paroxetine is accomplished in part by cytochrome CYP2D6.
Saturation of this enzyme at clinical doses appears to account for the
nonlinearity of paroxetine kinetics with increasing dose and increasing
duration of treatment. The role of this enzyme in paroxetine metabolism also
suggests potential drug-drug interactions (see PRECAUTIONS).

Approximately 64% of a 30 mg oral solution dose of
paroxetine was excreted in the urine with 2% as the parent compound and 62% as
metabolites over a 10-day post-dosing period. About 36% was excreted in the
feces (probably via the bile), mostly as metabolites and less than 1% as the
parent compound over the 10-day post-dosing period.

In a meta analysis of paroxetine from 4 studies done in
healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males
did not exhibit a significantly lower Cmax or AUC than females.

Distribution

Paroxetine distributes throughout the body, including the
CNS, with only 1% remaining in the plasma.

Protein Binding

Approximately 95% and 93% of paroxetine is bound to
plasma protein at 100 ng/ml and 400 ng/ml, respectively. Under clinical
conditions, paroxetine concentrations would normally be less than 400 ng/ml.
Paroxetine does not alter the in vitro protein binding of phenytoin or
warfarin.

Renal and Liver Disease

Increased plasma concentrations of paroxetine occur in
subjects with renal and hepatic impairment. The mean plasma concentrations in
patients with creatinine clearance below 30 ml/min was approximately 4 times
greater than seen in normal volunteers. Patients with creatinine clearance of
30 to 60 ml/min and patients with hepatic functional impairment had about a
2-fold increase in plasma concentrations (AUC, Cmax).

The initial dosage should therefore be reduced in
patients with severe renal or hepatic impairment, and upward titration, if
necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION).

Elderly Patients

In a multiple-dose study in the elderly at daily
paroxetine doses of 20, 30, and 40 mg, Cmin concentrations were about 70% to
80% greater than the respective Cmin concentrations in nonelderly subjects.
Therefore the initial dosage in the elderly should be reduced (see DOSAGE
AND ADMINISTRATION).

Drug-Drug Interactions

In vitro drug interaction studies reveal that paroxetine
inhibits CYP2D6. Clinical drug interaction studies have been performed with
substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of
drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine
(see PRECAUTIONS: DRUG INTERACTIONS).

Clinical Trials

Major Depressive Disorder

The efficacy of paroxetine as a treatment for MDD has
been established in 6 placebo-controlled studies of patients with MDD (ages 18
to 73). In these studies paroxetine was shown to be significantly more
effective than placebo in treating MDD by at least 2 of the following measures:
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and
the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine was
significantly better than placebo in improvement of the HDRS sub-factor scores,
including the depressed mood item, sleep disturbance factor, and anxiety
factor.

A study of outpatients with MDD who had responded to
paroxetine (HDRS total score < 8) during an initial 8-week open treatment
phase and were then randomized to continuation on paroxetine or placebo for 1
year demonstrated a significantly lower relapse rate for patients taking
paroxetine (15%) compared to those on placebo (39%). Effectiveness was similar
for male and female patients.

Obsessive Compulsive Disorder

The effectiveness of paroxetine in the treatment OCD was
demonstrated in two 12-week multicenter placebo-controlled studies of adult
outpatients (Studies 1 and 2). Patients in all studies had moderate to severe
OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive
Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a
dose-range finding study where patients were treated with fixed doses of 20,
40, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40
and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40
and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7
points, respectively, on the YBOCS total score which was significantly greater
than the approximate 4-point reduction at 20 mg and a 3-point reduction in the
placebo-treated patients. Study 2 was a flexible dose study comparing
paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this
study, patients receiving paroxetine experienced a mean reduction of
approximately 7 points on the YBOCS total score, which was significantly
greater than the mean reduction of approximately 4 points in the
placebo-treated patients.

The following table provides the outcome classification
by treatment group on Global Improvement items of the Clinical Global
Impressions (CGI) scale for Study 1.

Subgroup analyses did not indicate that there were any
differences in treatment outcomes as a function of age or gender.

The long-term maintenance
effects of paroxetine in OCD were demonstrated in a long-term extension to
Study 1. Patients who were responders on paroxetine during the 3-month
double-blind phase and a 6-month extension on open-label paroxetine (20 to 60
mg/day) were randomized to either paroxetine or placebo in a 6-month
double-blind relapse prevention phase. Patients randomized to paroxetine were
significantly less likely to relapse than comparably treated patients who were
randomized to placebo.

Panic Disorder

The effectiveness of paroxetine in the treatment of PD
was demonstrated in three 10- to 12-week multicenter, placebo-controlled
studies of adult outpatients (Studies 1-3). Patients in all studies had PD
(DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown
to be significantly more effective than placebo in treating PD by at least 2
out of 3 measures of panic attack frequency and on the Clinical Global
Impression Severity of Illness score.

Study 1 was a 10-week dose-range finding study: patients
were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A
significant difference from placebo was observed only for the 40 mg/day group.
At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic
attacks, compared to 44% of placebo-treated patients.

Study 2 was a 12-week flexible-dose study comparing
paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine
patients were free of panic attacks compared to 32% of placebo-treated patients.

In both Studies 2 and 3, the mean paroxetine dose for
completers at endpoint was approximately 40 mg/day of paroxetine.

Long-term maintenance effects of paroxetine in PD were
demonstrated in an extension to Study 1. Patients who were responders during
the 10-week double-blind phase and during a 3-month double-blind extension
phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in
a 3-month double-blind relapse prevention phase. Patients randomized to
paroxetine were significantly less likely to relapse than comparably treated
patients who were randomized to placebo.

Subgroup analyses did not indicate that there were any
differences in treatment outcomes as a function of age or gender.

Generalized Anxiety Disorder

The effectiveness of paroxetine in the treatment of
Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter,
placebo-controlled studies (Studies 1 and 2) of adult outpatients with GAD
(DSM-IV).

Study 1 was an 8-week study comparing fixed paroxetine
doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine
were both demonstrated to be significantly superior to placebo on the Hamilton
Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence
in this study to suggest a greater benefit for the 40 mg/day dose compared to
the 20 mg/day dose.

Study 2 was a flexible-dose study comparing paroxetine
(20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically
significant superiority over placebo on the Hamilton Rating Scale for Anxiety
(HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20
mg to 50 mg daily), did not demonstrate statistically significant superiority
of paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A)
total score, the primary outcome.

Subgroup analyses did not indicate differences in
treatment outcomes as a function of race or gender. There were insufficient
elderly patients to conduct subgroup analyses on the basis of age.

In a longer-term trial, 566 patients meeting DSM-IV
criteria for GAD, who had responded during a single-blind, 8-week acute
treatment phase with 20 to 50 mg/day of paroxetine, were randomized to
continuation of paroxetine at their same dose, or to placebo, for up to 24
weeks of observation for relapse. Response during the single-blind phase was
defined by having a decrease of ≥ 2 points compared to baseline on the
CGI-Severity of Illness scale, to a score of &e;3. Relapse during the
double-blind phase was defined as an increase of ≥ 2 points compared to
baseline on the CGI-Severity of Illness scale to a score of ≥ 4, or
withdrawal due to lack of efficacy. Patients receiving continued paroxetine
experienced a significantly lower relapse rate over the subsequent 24 weeks
compared to those receiving placebo.

Last reviewed on RxList: 11/24/2014
This monograph has been modified to include the generic and brand name in many instances.